The work projected for the next year is a continuation of the studies begun using the three different end points: 1) respiratory depression, 2) gastrointestinal transit of a charcoal meal, and 3) tail-flick analgesia. Values of K(B) and pA2 will be determined for each of these in vivo end points, utilizing the pharmacokinetic information (brain naloxone concentration-time data) that is necessary for the precise calculation of these constants. As explained in the original proposal, significant differences in these constants, determined from the three different effector systems, are indicative of different receptor types. The pharmacokinetics of naloxone is of value in its own right in the further development of models that describe opiate agonist-antagonist actions as a function of dose and time. In addition, work on the effect of chronic naloxone administration, a possible perturbation of opiate receptor-effector systems, will be expanded in order to assess its possible effect on affinity (-log K(B)). Work with the guinea-pig isolated ileum, not part of the original proposal, but subsequently valuable in our quantitative characterization of receptors, will be expanded to include other analgesics whose receptors have not definitively been differentiated.